Endocrine Disrupting Chemicals: Health Effects and Moving Forward - - PowerPoint PPT Presentation

National Institutes of Health U.S. Department of Health and Human Services

Endocrine Disrupting Chemicals: Health Effects and Moving Forward

Linda S. Birnbaum, Ph.D., D.A.B.T., A.T.S. Director National Institute of Environmental Health Sciences National Toxicology Program

Pesticides & The Chesapeake Bay Watershed Project Conference 18 September 2019 Reisterstown, Maryland

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Director: Linda S. Birnbaum, PhD, DABT, ATS Deputy Director: Rick Woychek, PhD

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Executive Officer: Chris Long, MPA

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Scientific Director: Darryl Zeldin, MD

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Scientific Director: Brian Berridge, DVM, PhD, DACVP

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Our Health

Image adapted from: NHGRI

Genetics

National Institutes of Health U.S. Department of Health and Human Services

Our Health

Image adapted from: NHGRI

Genetics + Environment

Combustion by-products Medicines Pesticides Personal care products Stress Chemicals in electronics Diet Microbiome Synthetic materials

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The Endocrine System

• Extremely complex, many

controls, interacting parts

• Multiple points of regulation for

finely-tuned responses

• Sensitive to perturbations
• Naturally operates at low

doses

• Effects can be activational

and/or organizational

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Endocrine Disrupting Chemicals: A Global Health Problem

Hormones EDCs Nuclear Receptors

• “An exogenous substance or mixture

that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact

• rganism, or its progeny, or (sub)

populations.”

• Report from The United Nations

Environment Programme (UNEP) and the World Health Organization (WHO), “State of the Science of Endocrine Disrupting Chemicals (EDCs)”

– EDCs are becoming a "global threat" that needs to be addressed

• WHO. State of the Science of Endocrine Disrupting Chemicals. 2013

National Institutes of Health U.S. Department of Health and Human Services

Endocrine Disrupting Chemicals (EDCs)

Known EDCs:

• Dioxin and dioxin-like compounds
• Polychlorinated biphenyls (PCBs)
• Some pesticides
• Plasticizers, such as BPA

Health outcomes associated with EDC exposure:

• Developmental
• Reproductive
• Neurological
• Immune

How do EDCs work? EDCs can mimic the body's natural hormones or alter the natural production of hormones

NIEHS, 2019

National Institutes of Health U.S. Department of Health and Human Services

Lifelong Effects of Early-Life Exposures

Developmental Origins of Health and Disease (DOHaD)

Chemical Contaminants in the Chesapeake Bay

Common contaminants:

– Polychlorinated biphenyls (PCBs) – Pesticides – Polycyclic aromatic hydrocarbons (PAHs) – Mercury – PFAS

Sources of contamination:

– Air pollution – Agricultural runoff – Stormwater runoff – Wastewater discharge Almost three-quarters of the Bay’s tidal waters are impaired by chemical contaminants, which can harm the health of both humans and wildlife

Chesapeake Bay Program, 2019

National Institutes of Health U.S. Department of Health and Human Services

Pesticides, Sources, and Health Effects

NIEHS, 2019. CDC, 2019

• Includes herbicides, fungicides,

insecticides, and disinfectants

• Sources include agricultural,

residential, and occupational

• Many health effects associated

with exposure, including:

– Cancer – Neurological (Parkinson’s disease, autism, IQ) – Endocrine and metabolic effects (diabetes) – Respiratory effects

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Maternal Pesticide Exposure and Autism in Children

• Finnish Prenatal Study
• f Autism

– Mothers with the highest DDE blood levels in early pregnancy were 32% more likely to have a child who developed autism (p=0.03)

• CHARGE Study (CA)

– Mothers living near agricultural pesticide applications had a 60% increased risk for a child developing autism

Brown et al., Am J Psychiatry, 2018. Shelton et al., EHP, 2014.

National Institutes of Health U.S. Department of Health and Human Services

Prenatal Organophosphate (OP) Exposure and Decreased Infant Motor Function

• 30 OPs measured in

umbilical cord blood

• Motor function

assessed at 6-weeks and 9-months in Chinese infants (N=199)

• Prenatal naled and

chlorpyrifos were associated with decreased motor function at 9-months

Silver et al., Environ Int, 2017

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Pesticides Associated with Neurobehavioral Effects in Ecuadorian Children

• Conducted behavioral

tests between 63 and 100 days after Mother’s Day

• Children tested closer to

Mother’s Day had lower neurobehavioral performance

• Periods of peak pesticide

use may transiently affect child neurobehavior

Suarez-Lopez et al., NeuroToxicology, 2017

Days after Mother’s Day Harvest Neurobehavioral Score

N = 308 children 4-9 years old

National Institutes of Health U.S. Department of Health and Human Services

Developmental Pesticide Exposure Induces Neuroinflammation, Reduces Spatial Learning

• Rats exposed from

GSD 7 to PND 21

• All pesticides induced

neuroinflammation, increasing IL-1b in hippocampus

• Effects were pesticide

and sex-specific

IL-1b (% control)

Working Memory

Gómez-Giménez et al., Food and Chem Toxicol, 2017

Working errors

Pesticide Dose (mg/kg/day) Cypermethrin 1.5 Endosulfan 0.5 Carbaryl 15 Chlorpyrifos 0.1, 0.3, & 1

Exposure to Agricultural Pesticides and Cancer

Among participants enrolled in the Agricultural Health Study:

• Use of chlorpyrifos and terbufos was associated with increased

breast cancer risk among farmer’s wives

(Engel et al., Environ Health Perspect, 2017)

• Use of pendimethalin, dieldrin, parathion, and chlorimuron ethyl

associated with lung cancer risk in farmers

(Bonner et al., Environ Health Perspect, 2017)

• Use of the herbicide alachlor was associated with laryngeal cancer

and myeloid leukemia in pesticide applicators

(Lerro et al., J Natl Cancer Inst, 2018)

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Pesticides and Respiratory Symptoms in Farmers

• Assessed pesticide exposures and wheeze among male participants

in the Agricultural Health Study (N=22,134)

• Of 78 pesticides

examined, 21 were significantly associated with non-allergic wheeze, and 19 with allergic wheeze

• Dose-response

relationships observed for three commonly used herbicides: glyphosate, 2,4-D, and atrazine

Hoppin et al., Environ Health Perspect, 2017

DDT and Breast Cancer: The Timing of Exposure Matters

• Evaluated timing of DDT exposure and breast cancer
• DDT was associated with breast cancer through age 54
• Risk depended
• n timing of first

exposure

• DDT may be an

endocrine disruptor with responsive breast targets from in utero to menopause

DDT associated breast cancer by age at first exposure and age at diagnosis

Cohn et al., J Natl Cancer Inst, 2019

National Institutes of Health U.S. Department of Health and Human Services

Pesticides and Endocrine Effects

Organochlorine pesticides: Associated with reduced BMI and height in 8 to 19-year-old boys

(Sergeyev et al., Rev Environ Health, 2017)

Organophosphate pesticides: Associated with altered testosterone levels in Thai farmworkers

(Panuwet et al., Arch Environ Occup Health, 2018)

Pesticide residue on food: May reduce probability of pregnancy and live birth following assisted reproduction approaches

(Chiu et al., JAMA Intern Med, 2018)

Photo by Josh Vogel, Maryland Dept. of Natural Resources

Polychlorinated Biphenyls (PCBs)

• Used in hundreds of industrial and commercial applications
• Banned in U.S. in 1979
• Mobile, persistent, and accumulate in the environment and

wildlife

• Associated with a range of health effects:

– Cancer – Immune – Reproductive – Nervous – Endocrine

EPA, 2018

National Institutes of Health U.S. Department of Health and Human Services

Early Life PCB Exposure Effects Multiple Systems

• Higher prenatal PCB exposure

associated with autism spectrum disorder (Lyall et al., EHP,

2017)

• Prenatal PCB exposure

associated with increased levels of sex hormones in 12- year-old boys (Eskenazi et al., Int J Hyg

Environ Health, 2017)

• Boys with the highest levels
• f serum PCBs had early
• nset puberty (Burns et al., EHP, 2016)
• Infants with highest PCB

exposure had 37% lower response to tuberculosis vaccine compared to lowest exposure group (Jusko et al., EHP, 2016)

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Per- and Polyfluoroalkyl Substances (PFAS)

• Group of nearly 5,000

chemicals

• Mobile, persistent, and

accumulate in the environment

• Resistant to grease,

water, and oil

• Emergence of alternatives

which are less well studied

PFMOAA PFOA PFOS GenX

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PFAS Exposure Pathways

Sunderland et al., J Expos Sci & Epidemiol, 2019

PFAS Health Effects

PFAS exposure has been associated with:

• Altered immune function
• Cancer
• Decreased birthweight
• Liver effects
• Metabolic outcomes
• Neurodevelopmental
• utcomes
• Thyroid disruption

Savitz et al., Environ Health Perspect, 2012; Sunderland et al., J Expos Sci & Epidemiol, 2019

PFOS (ng/mL) OR (95% CI) of T2D

Positive relationship between PFOS and risk of type 2 diabetes.

Sun et al., Environ Health Perspect, 2018

Higher PFNA was associated with poorer executive

• functioning. Vuong et

al., Environ Int, 2018

Measure of executive function

National Institutes of Health U.S. Department of Health and Human Services

PFAS Levels Associated with Altered Kidney and Thyroid Function

• Repeated measures of

serum PFOS associated with increased thyroid stimulating hormone

• Repeated measures of

serum PFNA, PFHxS, and PFDeA associated with decreased kidney function

• PFHxS retained high stability between serum measurements
• ver a period greater than 10 years

Blake et al., Environ Pollut, 2018

Phthalates

• Large group of chemicals

used to make plastics more soft and flexible

• Found in food contact

materials and food processing equipment

• Diet is a significant source of

exposure for certain phthalates, especially DEHP

• Phthalates enter our food

through packaging, processing, and handling

Varshavsky et al., Environ Int, 2018

DEHP DiNP DiDP

Phthalate Health Effects

• Endocrine outcomes
• Reproductive
• utcomes
• Fetal development
• Obesity
• Neurodevelopment
• Cancer
• Diabetes and

insulin resistance

• Immune system

and allergic disease

Benjamin et al., J Haz Materials, 2017

Q1 Q2 Q3 Q4 Q5

ΣDEHP Odds Ratio (95% CI)

10 1

ADHD increases with prenatal DEHP exposure

Modified from: Engel et al., EHP, 2018

Monobenzyl phthalate correlated with decreased sperm motility

Thurston et al., Andrology, 2016

Odds Ratio

Prenatal exposure to some phthalates associated with increased child BMI

Modified from: Harley et al., Pediatr Res, 2017

MEP MBP MiBP MBzP ΣDEHP

Phthalates, Anogenital Distance and Sperm Count

• Male Anogenital Distance (AGD) strongly

correlates with all semen parameters and is a predictor of low sperm concentration.

• In animals, male AGD at birth reflects

androgen levels during masculinization programming window and predicts adult AGD and reproductive function.

• Androgenic environment during early fetal

life exerts fundamental influence on both AGD and adult sperm counts in humans.

• Data support the hypothesis that

prenatal phthalate exposure at environmental levels adversely affects male reproductive development.

Mendiola et al, 2011. EHP;119:958–963

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Prenatal Phthalate Exposure Associated with Birth Defects in Mice

• Pregnant mice were exposed to 0, 5, 250, or 500 mg/kg DEHP
• DEHP had major effects on fetal

survival and development:

Ungewitter et al., Toxicol Sci, 2017

– Reduced rate of fetal survival – Increased incidence of limb malformations and neural tube defects – Altered expression of genes important in male reproductive development

Prenatal DEHP exposure led to a birth defect of additional digits in this mouse hind limb (black arrows).

National Institutes of Health U.S. Department of Health and Human Services

Phthalate Exposure Before Birth May Hinder Brain Development

• Female rats were exposed to

phthalate mixture throughout pregnancy and for 10 days during lactation

• Adult offspring of exposed rats

had a smaller medial prefrontal cortex with fewer neurons and synapses

• Rats with fewer overall

synapses were less cognitively flexible than those with more synapses

Kougias et al., J Neurosci, 2018

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Bisphenol-A (BPA)

• Used to produce polycarbonate

plastics and epoxy resins

• >8 billion pounds produced annually
• Found in:

– Food packaging, consumer and medical products – Thermal receipt paper – Industrial emissions – Metal and plastic equipment and appliances

National Institutes of Health U.S. Department of Health and Human Services

BPA Health Effects

BPA exposure has been associated with:

• Increased risk of obesity

and type 2 diabetes

• Poor reproductive
• utcomes (e.g., ovary

and uterine function and sperm quality)

• Higher levels of anxiety,

depression, aggression, and hyperactivity in children

Legeay et al., Fundam Clin Pharmacol, 2017; Hwang et al., BMC Endcrine Disorders, 2018; Ejaredar et al., J Expos Sci Environ Epidemiol, 2017

Log BPA (ng/mL)

Measure of insulin resistance Direct association between urinary BPA levels and insulin resistance in obese children

(Adapted from: Menale et al., Pediatr Obes, 2017)

National Institutes of Health U.S. Department of Health and Human Services

Moving Forward: Research Needs and Reducing Exposures

• Assess health and

environmental effects of alternative chemicals

• Consider health effects of

complex chemical mixtures

• Develop and promote

strategies individuals and communities can use to reduce exposures

National Institutes of Health U.S. Department of Health and Human Services

Real-World Exposures Occur As Mixtures

• We are all exposed to a mixture
• f chemical and non-chemical

stressors

• Mixtures can produce health

effects greater than each exposure alone

• Studying mixtures requires

evaluation of:

– Individual chemicals within the mixture – Interactions between those chemicals – Combined effect of mixture

• n health

EDC Mixtures and Gestational Diabetes

• Examined associations

between EDCs – individually and in combination – on gestational diabetes risk during pregnancy – Looking at parabens individually yielded no significant results – Looking at parabens as a chemical mixture showed a positive association

Bellavia et al., Environ Res, 2019

Differences in glucose in mg/dL as a function of 1st trimester paraben

• concentrations. Point estimates for

exposure changes between the 10th and 90th percentile of their distribution.

National Institutes of Health U.S. Department of Health and Human Services

Technology & Application Contaminant PI, Org, Grant Biochar to sequester contaminants in aquifers Dioxins

• S. Boyd,

Michigan State University Magnetic nanocomposites for water remediation PCBs

• Z. Hilt,

University of Kentucky Functionalized membrane filters for groundwater remediation PCBs D.B. Bhattacharyya, University of Kentucky Activated carbon to immobilize contaminants in aquatic ecosystems PCBs, Mercury

• U. Ghosh

U Maryland, Baltimore Poplar trees to remove chemicals from soil and water PCBs

• J. Schnoor,

University of Iowa Controlled release polymers for contaminated aquifers PAHs

• A. Carpenter,

AxNano Combined in situ/ex situ expedited aquifer remediation PFAS

• R. Ball,

EnChem Engineering

NIEHS grantees develop new technologies and approaches to clean up contaminants in water, sediment, and soil

Cleaning up Contaminants in the Environment

National Institutes of Health U.S. Department of Health and Human Services

Activated Carbon Reduces Bioaccumulation

• f EDCs
• Activated carbon is a porous,

manufactured material created from coal or wood

• Tested ability of granular activated

carbon (GAC) and pelletized fine activated carbon (PfAC) to limit bioaccumulation in contaminated sediments

• Measured organochlorines in the

blackworm (Lumbriculus variegatus)

• PfAC significantly limited

bioavailability and reduced worm body burdens

Dang et al., Chemosphere, 2018

Worm body burden (ng/g ww)

no AC with GAC with PAC

Triclosan

Worm body burden (ng/g ww)

no AC with GAC with PAC

Triclocarban

National Institutes of Health U.S. Department of Health and Human Services

Green Infrastructure to Reduce Stormwater Runoff

• Researchers modeled benefits of installing green

infrastructure on vacant lots in three flood-prone Houston neighborhoods

• Analysis showed that the designs would capture 7-40 million

gallons of stormwater per year

• Additional benefits: More tree coverage,

walkable space, and green space

Newman et al., Landsc Archit Front, 2019

Stormwater runoff is the fastest growing source of pollution in the Chesapeake Bay

(Chesapeake Bay Program, 2019)

National Institutes of Health U.S. Department of Health and Human Services

Reducing Pesticide Exposure

• Break the take-home pathway:

Farmworkers can reduce pesticide exposure to their families by wearing gloves, washing hands, and removing work clothes before returning home

• Use an IPM Approach:

An integrated pest management (IPM) approach can be used in agricultural and non-agricultural settings to reduce direct exposures and pesticide runoff

NIEHS/EPA Children’s Centers Impact Report, 2017

Thank You! Any Questions?